CD96 Gene: Function, Mutations, and Role in C Syndrome & Cancer

CD96 (T cell activation, increased late expression) is a protein-coding gene located on chromosome 3q13.13-q13.2. It encodes a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily, primarily expressed on natural killer (NK) cells and activated T cells. CD96 functions as an immune checkpoint receptor, binding to nectin and nectin-like proteins (e.g., CD155) to modulate NK cell adhesion, cytotoxicity, and cytokine production. Mutations in CD96 are associated with C syndrome (Opitz trigonocephaly-like syndrome), and the gene is a target for cancer immunotherapy due to its role in tumor immune evasion.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Immune checkpoint signaling (CD96-CD155 interaction)

• Natural killer cell mediated cytotoxicity (KEGG hsa04650)

• Cell adhesion molecules (CAMs) (KEGG hsa04514)

CD96 is a 585-amino acid type I transmembrane glycoprotein with three extracellular immunoglobulin-like domains (V-set, C2-set, and C2-set), a transmembrane region, and a cytoplasmic tail containing ITIM-like motifs. It is expressed on NK cells and activated T cells, where it binds to CD155 (PVR) and nectin-1 to regulate cell adhesion, NK cell cytotoxicity, and cytokine secretion. CD96 competes with CD226 (DNAM-1) for CD155 binding, acting as an inhibitory checkpoint. The protein is encoded by the CD96 gene on chromosome 3q13.13-q13.2, with UniProt ID Q96NY8.